In modern medical diagnosis, strips referred to as diagnostic test strips are being used for an increasingly large number of analytical test strips. These diagnostic test strips can be used, for example, to determine the level of glucose, cholesterol, proteins, ketones, phenylalanine or enzymes in biological fluids such as blood, saliva and urine.
The most frequently encountered application of diagnostic test strips is the determination and monitoring of blood sugar level among diabetics. Roughly 175 million people worldwide suffer from diabetes mellitus type 1 and type 2. The trend in this condition is rising.
Many sufferers from this incurable disease monitor their blood sugar level up to 5 times a day in order to obtain the best match between the dosage of the medication (insulin) and the consumption of food, since an excessive blood sugar level inevitably makes health-related damage likely. Hitherto diabetics relied on the support of medical staff in order to determine the blood sugar level. To greatly simplify the monitoring of the blood sugar level a test was developed which enables the diabetic to determine his or her own blood sugar level with a minimum of effort and without reliance on medical staff.
To determine the blood sugar level the tester has to apply a drop of blood to a diagnostic test strip. During this procedure the diagnostic test strip is located in a read device or evaluation device. Following a reaction time or response time the evaluation device indicates the current blood sugar level. Read or evaluation devices of this kind are described for example in U.S. Pat. No. 5,304,468 A, EP 1 225 448 A1, and WO 03/08091 A1.
One of the first patents in the technical field of test strips appeared back in 1964. U.S. Pat. No. 1,073,596 A describes a diagnostic test and the test strips for analyzing biological body fluids, especially for determining blood sugar. The diagnostic test functions via the determination of a color change which is triggered by an enzyme reaction.
Determining a change in the concentration of a dye (colorimetric method) is still a method used today in the determination of blood sugar using diagnostic test strips. The enzyme glucose oxidase/peroxidase reacts with the blood sugar. The hydrogen peroxide formed then reacts with the indicator O-toluidines, for example—which leads to a color reaction. This color change can be monitored by colorimetric methods. The degree of change in color is directly proportional to the concentration of blood sugar. In this case the enzyme is located on a woven fabric. This method is described for example in EP 0 451 981 A1 and WO 93/03673 A1.
The modern development of diagnostic test strips aims to reduce the measurement time between the application of the blood to the test strip and the appearance of the result. The measurement time, or the time between the application of the blood to the diagnostic measurement strip and the display of the result, is dependent not only on the actual reaction time in the enzymic reaction and in the follow-on reactions but likewise, to a considerable extent, on the time taken for the blood to be transported within the diagnostic strip from the blood application site to the reaction site, in other words to the enzyme.
One of the ways in which the measuring time is reduced is by the use of hydrophilicized woven or nonwoven fabrics, as in U.S. Pat. No. 6,555,061 B, in order to transport the blood more quickly to the measuring area (enzyme). The measuring method is identical with that described in EP 0 451 981 A1. In the construction of the diagnostic strips a double-sided standard adhesive tape, Scotch® 415, is used. Surface-modified woven fabrics having a wicking effect for the biological fluid are described in WO 93/03673 A1, WO 03/067252 A1, and US 2002/0102739 A1. In the last citation, plasma treatment of the woven fabric produces a blood transport rate of 1.0 mm/s. With the use of woven fabrics for the transport of the biological test fluid such as blood, for example, a chromatography effect is observed, however; in other words, the individual constituents, such as cells, are separated from the liquid constituents. The chromatography effect is exploited explicitly in WO 03/008933 A2 for the purpose of separate analysis of the blood constituents.
An onward development from the colorimetric measurement technique is the electrical determination of the change in oxidation potential an electrode coated with the enzyme. This method and a corresponding diagnostic test strip are described in WO 01/67099 A1. The diagnostic strip is constructed by printing various functional coats, such as electrical conductors, enzyme, and hot-melt adhesive, onto the base material, which is of polyester, for example. Subsequently, an otherwise unspecified hydrophilic film is laminated on by thermal activation of the adhesive. The purpose of the hydrophilic film is to accelerate the transport of the blood to the measuring cell.
With this construction there is no need for woven or nonwoven fabric to transport the blood. The advantage of this construction and the advantage of the new measuring technique is that the blood sugar level can be measured with a very much smaller volume of blood, around 5 to 10 μl, and in a shorter measuring time.
U.S. Pat. No. 5,997,817 A describes an electrochemical biosensor in which the transport of the biological fluid is realized likewise by way of a hydrophilic coating. The coating in question is ARCARE 8586 (not available commercially) from Adhesive Research Inc. The transport of the biological fluid is evaluated in a specific capillary test of which no further details, however, are given.
DE 102 34 564 A1 describes a biosensor which is composed of a planar sensor or test strip and a compartmentalized reaction and measuring-chamber attachment produced by embossing a PVC film. The measuring-chamber attachment is composed of a very specific embossed design comprising sample application duct, measurement chamber, sample arrest duct, and sample collection space. The embossed depth of this compartmentalization amounts to 10 to 300 μm. The sample application duct and the measurement chamber are furnished with a woven hydrophilic fabric or with a surfactant coating for the transport of the biological fluid.
DE 102 11 204 A1 describes a flow-through measuring cell for the continuous determination of glucose. The measuring cell is composed of a planarly structured film which forms a small inlet duct and a substantially large outlet duct, the two ducts opening into one another by way of a defined angle.
U.S. Pat. No. 5,759,364 A describes an electrochemical sensor which is composed of a printed base plate and an embossed cover film of PET or polycarbonate. The concavely embossed cover film forms the measuring chamber and accommodates the enzyme for the detection reaction. For rapid blood transport the underside of the embossed cover film is coated with a hydrophilic polymer formed from a polyurethane ionomer.
In the majority of cases the diagnostic test strips described are produced by means of a discontinuous sequence of coating of laminating steps. The base material used is a 300 to 500 μm thick film of polyvinyl chloride, polyester or polycarbonate with dimensions of approximately 400×400 mm. For the functional capacity of the biosensors it is necessary to implement diecuts, some of them very complex, on the different materials or to process very complex diecut forms of, for example, pressure-sensitive adhesive (PSA) tapes. The result of this is a production operation which is complicated and slow in some cases. For some time now there have also been approaches at producing the diagnostic strips in continuous methods. The coating and laminating steps are commonly followed by a series of slitting operations. Owing to the small dimensions of the diagnostic strips, of approximately 20 mm×5 mm, the utmost precision is needed in the course of the coating, laminating, and slitting operations. Slitting to form the diagnostic strips is typically accomplished with very high cycle rates, using slitting machines obtained, for example, from Siebler GmbH or from Kinematik Inc.
In the course of the slitting operations it is possible for problems to arise to a considerable extent. When unsuitable materials, which exhibit inadequate adhesion to one another in the course of lamination, are used delamination in the slitting operation is observed continually. This inadequate adhesion may be attributed to an unsuitable adhesive, i.e., an adhesive having a very high shear strength, to an unsuitable bonding substrate, or to an unsuitable coating of the bonding substrate. Typical coatings with surface-active substances such as, for example, surfactants for the purpose of hydrophilicizing surfaces often lead to these delamination problems in the slitting operation. Relatively good strength of adhesion on the different bonding substrates is obtained if commercially customary pressure-sensitive adhesive tapes with low or moderate shear strength are used. In this case, however, instances of contamination of the slitting tool by residues of adhesive occur after just a short time. This contamination after just a few hours has already reached a level where the blades, drive units, and guide rails of the slitting machine must be changed over wholesale and cleaned. This gives rise to considerable maintenance and downtime costs.
The residues of adhesive mentioned are attributable to the commercially customary self-adhesive tapes employed. The use of non-self-adhesive hot-melt adhesives or heat-sealing adhesives such as those based, for example, on polyamides, polyisobutylene, polyvinylbutyral, polyesters, poly(ether sulfone)s, ethylene/ethyl acrylate copolymers or ethylene/vinyl acetate copolymers achieves a significant lengthening in the cleaning intervals.
When hot-melt adhesives are used, however, considerable disadvantages are observed in the construction of the diagnostic test strips. Activation of the hot-melt adhesives requires pressure and temperatures of at least 80° C. Under these conditions on the one hand there is a risk of thermal damage to the enzyme layer and to one of the woven or nonwoven fabrics used, and on the other hand it is impossible to realize a uniform and accurate distance between the functional layers such as base film, woven fabric and outer film of the diagnostic test strip. The distance between the functional layers determines the blood volume which is used for the measurement. If there are fluctuations in the blood volume as a result of an excessive range of fluctuation in the distance between the functional layers across—for example—different batches of test strips it is impossible to determine the blood sugar level reliably.
It is an object of the present invention to provide a medical biosensor by means of which biological fluids are analyzed, which in particular in the slitting operation during production leads to a considerable reduction in the residues of adhesive on the slitting tools, and which also ensures rapid transport of the biological fluid and hence a short measurement time.